Chaperone a Dance around Alzheimer’s

A collaboration of scientists from across Europe has discovered a cellular pathway that could lead to the development of new therapeutic interventions to stop or severely slow the progression of Alzheimer’s disease (AD). The researchers found that a molecular chaperone naturally occurring in humans could disrupt the formation of amyloid plaques, which are commonly associated with AD dementia.

The research was carried out by an international team of scientists from the University of Cambridge, the Karolinska Institute, Lund University, the Swedish University of Agricultural Sciences, and Tallinn University in Estonia. The results from this study were published in Nature Structural & Molecular Biology through an article entitled “A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers”.

The scientists found that the human chaperone called Brichos was able to interrupt the aggregation of the amyloid-β pepetide (Aβ42). Previous studies have shown that the surfaces of Aβ42 catalyze the formation of oligomers, which effectively form neurotoxic plaques.

The research teams observed that in vitro, Brichos was able to inhibit Aβ42 oligomerization, thereby severely hindering the catalytic cycle leading to plaque formation. Specifically, the investigators found that Brichos binds to the surface of Aβ42 fibrils and redirects the aggregation reaction toward a pathway that leads to marginal formation of toxic oligomeric intermediates.

The investigators were also able to show that mice given injections of amyloid proteins directly to their brains, in order to mimic AD pathology, showed a reduction in normal electrical activity, which is indicative of the neurotoxic effects of amyloid plaques. However, co-injections of amyloid proteins and Brichos lead to a protective phenotype that was unrecognizable from control mice.

“These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation,” stated the scientists.

Although Brichos may be difficult to convert into a therapeutically viable compound for the treatment of AD, the scientists are optimistic that their current findings show that the neurotoxic effects associated with amyloid plaques can be disrupted.

“A good tactic now is to search for other molecules that have this same highly targeted effect and to see if these can be used as the starting point for developing a future therapy,” concluded Samuel Cohen, Ph.D., research fellow at St. John’s College, Cambridge and lead author on the current study.